Abstract The progression and timing of events leading to Alzheimer?s disease (AD) pathology is varied and influenced by life history and genetic interactions. NRF2 is a cytoprotective transcription factor that plays established dose dependent roles in AD. As such, the degree of NRF2 activity can impact AD pathology and new mechanisms to control NRF2 are needed. We have identified a novel mechanism of NRF2 regulation by the WDR23 receptor for the CUL4-E3 ubiquitin ligase, which operates independently of KEAP1. This finding is critical as Keap1(-/-) animals are inviable at weaning, while our Wdr23(-/-) animals, with NRF2 activation, are viable. The central hypothesis driving our proposal is that mice genetically depleted of WDR23, which have activated NRF2, will reduce the accelerated progression of AD in the 3x-TgAD mouse model. Importantly, WDR23 has additional substrates that it delivers to the proteasome, which implies altering WDR23 could also have NRF2-independent effects. We will identify both should they exist. Remarkably, Wdr23(-/-) mice retain hippocampal-dependent behaviors typically lost with AD, but these animals also carry more fat and are have deregulated glucose homeostasis as compared to wild type controls. We suggest the activation of NRF2 in these Wdr23(-/- ) mice drives both of these phenotypes; i.e. NRF2 activation protects against AD, but at the cost of metabolic homeostasis. This model suggests a clear difference in the age-related pathologies of metabolic tissues as compared to the brain being regulated by a single genetic locus. To test our hypotheses, we propose three specific aims: In Aim 1 we will define the affect that loss of WDR23 has on canonical AD pathology that occurs with age; in Aim 2, we will interrogate the relationship that diet and adiposity play in AD pathology, in the background of NRF2 activation stemming from loss of WDR23; and in Aim 3, we will define the age-related changes to NRF2-dependent and ?independent transcripts in the hippocampus of brains with progressive AD pathology. Although WDR23 is a component of cellular proteostasis machinery, which is important for healthy brain aging, our preliminary studies support a protective response to WDR23 loss, via NRF2 activation. Our studies will identify the effects of WDR23 loss on AD and define potential mechanisms of action. The successful completion of the proposed research will be of great biological significance, accelerate our understanding of the molecular basis of AD, and define a role for a novel locus, WDR23, in AD pathology; all of which are central for the development of therapies of AD and other age-related neurodegenerative disease.